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Pharm Biomed Res 2017; 3(3):1

Utilization of curcumine and nanocurcumine compounds in

cancer therapy

Vajiheh Alinezhad1, Heshmatollah Alinezhad1, Ramin Ataee2*, Amin Ataie3 1Faculty of Chemistry, University of Mazandaran, Babolsar, Iran 2Thallassemia Research Center, Pharmaceutical Sciences Research Center, Hemoglobiopathy Institute, Mazandaran University of Medical Sciences, Sari, Iran

3Deparment of Pharmacology and Physiology, Babol University of Medical Sciences, Babol, Iran

A R T I C L E I N F O A B S T R A C T *Corresponding author: raminataee1349@gmail.com

Curcumin is a polyphenol extracted from the Curcuma plant. Curcumin has been used widely in ayurvedic medicine for centuries; it has a variety of biological properties including anti-oxidant, analgesic, anti-inflammatory and antiseptic activity. Curcumin has shown anti-cancer activities through variety of biological pathways engaged in mutagenesis, oncogene expression, cell cycle regulation, apoptosis, tumorigenesis and metastasis. Curcumin has proved anti-proliferative effect in many cancers, and is an inhibitor of the transcription factor NF-κB and downstream gene products (including c-myc, Bcl-2, COX-2, NOS, Cyclin D1, TNF-α, interleukins and MMP-9). Furthermore, curcumin affects a variety of growth factor receptors and cell adhesion molecules involved in tumor growth, angiogenesis and metastasis. However, a limiting factor is its extremely low bioavailability which hinders its use as therapeutic agent. Therefore, many technologies have been developed to overcome this limitation. We summarize to develop curcumin delivery aims and increase solubility for improving curcumin bioavailability and anticancer potential for therapy.

Article history: Received: Aug 24, 2017 Accepted: Sep 28, 2017

Keywords: Curcumin, apoptosis, anti-proliferative, metastasis, anti-inflammatory, antiseptic activity

Citation: Pharm Biomed Res 2017;3(3):1-11.

Introduction The continual reduction in cancer death rates over two decades has resulted in an overall drop of 23%, resulting in more than 1.7 million cancer deaths prevented. In spite of this development, cancer is now the leading cause of death for much of the US population (1,2). In 2016, an estimated 1,685,210 new cases of cancer will be diagnosed in the United States and 595,690 people will die from the illness. Current chemotherapeutic factors, such as alkylating agents, anti-metabolites, topoimerase inhibitors, and DNA intercalates, target a particular route, so finally dwindles tumor size but often fails to eradicate tumors or prevent their recurrence. Repeated therapy with these agents eventually causes tumors that become resistant to the chemotherapies. So, it is important to identify ‘natural products ’which have growth inhibitory and apoptosis induction properties on human cancer cells and that target multiple cellular signaling paths without resulting in toxicity issues in normal cells. A comprehensive review of the literature texts characterized curcumin as an excellent molecule among many naturally occurring compounds for cancer therapy (3). There are three primary curcuminoids which constitute curcumin: curcumin (curcumin A, 75%), demethoxycurcumin (curcumin B, 20%), and bisdemethoxycurcumin

(curcumin C, 5%; and our own analysis) (Fig. 1) (4).

Chemically, curcumin is a diarylheptanoid, belongs to the group of curcuminoids, that are natural phenols responsible for turmeric's' yellow color. This is a tautomeric combination existing in enolic form in organic solvents and as a keto form in water (5).

Review

PBR

Available online at http://pbr.mazums.ac.ir

Pharmaceutical and Biomedical Research

Figure 1 Chemical structures of curcumin (A),

demethoxycurcumin (B) and bisdemethoxycurcumin (C).

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Figure 2 Curcumin targets the classical hallmarks of cancer.

Research during the last two decades has indicated curcumin to be a strong antioxidant, anti-inflammatory, anti-proliferative, anti-metastatic, anti-angiogenic, anti-diabetic, hepatoprotective, anti-atherosclerotic, anti-thrombotic, and anti-arthritic agent in cell culture and animal studies (6). A serious limiting factor of curcumin is its low solubility in water (i.e. 0.0004 mg/ml at pH 7.3) and soluble curcumin molecules are much sensitive at physiological pH (7–8). Removing the limiting factors of curcumin to improve its bioavailability, should prevent from degradation and metabolism,

and increase its targeting capacity toward cancer tumor(s). Curcumin is available in various types of nanoparticle (NPs), such as polymer NPs, polymeric micelles, liposome phospholipid, nano-microemulsions, nanogels, solid lipid NPs, polymer conjugates, self-assemblies, and so on, which are proper for the delivery of an active form of curcumin to tumors (9). Anti-cancer Activity Curcumin has been examined in multiple human carcinomas including melanoma, head and neck,

Curcumin

Angiogenesis & Metastasis

Cox-2 MMP-9 MMP-10 VEGF

Cell Cycle Arrest

P16 CDK inhibitors

P53 Cyclin D1

P14ARF Cyclin E Other growth factors IL-6 IL-8

Apoptosis

P53 Bcl-2

Bax Bcl-xL

Bad NFkB

Bim pAkt mTOR

Autophapy

Lysosomal proteases

Phosphatases,

Lipases

IkKB

NFkB

Increased Transcription of TNF-α, COX-2, Cyclin D1, C-myc, MMP-9, IL-6, IL-8 And others

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breast, colon, pancreatic, prostate and ovarian cancers (10-18). It is good point of curcumin that can inhibit all primary abilities of cancer cells and restrict the consequence of tumor progression in the host (19). The expression of nuclear factor NFκB that controls cell proliferation, metastasis, angiogenesis, apoptosis and resistance to chemotherapy, is prevented by curcumin (20). Curcumin-induced down-regulation of NF-κB is mediated via suppression of IκB kinase activation. The proliferation signaling cascades such as PI3K, AKT, mTOR, AP1 (JUN and FOS), JNK, JAK-STAT, PKC, CMYC, MAPK, ELK, CDKs, iNOS and Wnt/β-catenin which are also suppressed by curcumin further confirmed that it is one of the crucial molecule that hinders cancer promotion by targeting multiple cell proliferation signaling. Curcumin also down-regulates the expression of Cyclin D1, the proto-oncogenes that are overexpressed in various types of cancer and plays a definite role in cell cycle progression and proliferation (21, 22). TP53 is the most important protein that manages on central regulatory circuits which controls the decision of cells whether to proliferate or undergo active ageing and provokes apoptosis schedule. Different researches in vitro and in vivo have been proved that curcumin upregulates the expression of TP53 and provokes apoptosis (23). On the other hand, curcumin also inhibits phosphorylation of RB (Retinoblastoma), another serious tumor suppressor protein that also plays an important role in cell cycle process (24). Curcumin inhibits EGF- and EGFR-mediated signaling path that is overexpressed in breast tumor and is involved in cancer advancement (25, 26). Curcumin also blocks excessive TGFβ receptor signaling that prompts epithelial to mesenchymal transition during offensive and metastasis (27, 28). During tumor development, TP53 is reduced so hindering its critical action as damage sensor and activator of apoptosis-inducing circuitry. On the other hand, tumors may attain similar sequels by increasing expression of anti-apoptotic regulators (BCL-2, BCL-XL) or survival signals (IGF1/2), or down regulating pro-apoptotic agents (BAX, BIM, PUMA), or by short-circuiting the extrinsic ligand-induced death path (29). Curcumin prompts both TP53-dependent and -independent cancer cell apoptosis. curcumin upregulates the pro-apoptotic molecules such as BAX, BIM, PUMA, whereas, curcumin down-regulates anti-apoptotic partners like BCL2, BCL-XL, Survivin,so that, curcumin simultaneously activates Caspases and induces apoptosis or programmed cell death (30, 31). Lysosomal proteases, phosphatases and lipases that provoke autophagy-mediated cell death, are activated by curcumin (32, 33). Generally, neo-

angiogenesis process is managed by the angiogenic factors such as VEGF and angiopoietin inducement. VEGF and angiopoietin overexpression factors are restricted by curcumin, that hinders angiogenesis process by clipping food and oxygen supply to the cancer cells (34). VEGF receptor (VEGFR1 and VEGFR2) expression is inhibited by curcumin, thereby blocking VEGF/VEGFR-mediated signalling pathway to restrict angiogenesis (23). Besides human telomerase (hTERT) activities, down-regulation hTERT-mRNA expression leading to telomere shortening is inhibited by curcumin. Thus curcumin targets telomerase activities and controls replicative cell senescence and mortality which finally regulate uncontrolled cell proliferative potential of cancer (35). Curcumin down-regulates several attacks, cell adhesion and extracellular matrix molecules such as matrix metalloprotease, CCRX4, COX2, ELAM1, ECAM1 which are essential for maintaining metastasis (36). In addition, several research also proposed that curcumin hampers the activities of SLUG, SNAIL, FAK, TWIST and other urgent transcription factors that play a crucial role in metastasis process (37). Lately, it was indicated that curcumin inhibits breast cancer stem cell migration by amplifying E-cadherin/beta-catenin negative feedback ring (Fig. 2) (38). Curcumin nanoformulations In spite of, curcumin activities as a potent immune-modulator, there are some of the major hurdles that hinders its efficacy as a chemotherapeutic drug against cancer such as poor water solubility, low bioavailability, lack of dose–response proportionality, uncontrolled precipitation, use of excessive co-solvents, necessity of extreme condition to solubilize (basic or acidic) and incompatibility to the patients (39, 40). Nanotechnology-based drug delivery systems have proven to be reliable and promising approach, to overcome this inconveniences. Poor bioavailability, enhance biological activities and also selectively target cancer cells are improved by nanotechnology-based drug delivery systems. Now it is possible to deliver the active pharmaceutical component as reduced nano-sized particles, ranging in size from 10 to 1000 nm, to enhance systematic bioavailability of higher molecular weight drugs. The nanotechnology-based drug delivery system has proven as a most effective manner to successfully deliver insoluble drugs with enhanced bioavailability (41). The decrease of particle size of active ingredients significantly enhances the dissolution rate resulting in higher bioavailability. Various kinds of nanoparticles are being expanded for successful encapsulation of curcumin. These contain liposomes, micelles, nanoparticles, nanoemulsions, nanogels, nanocrystal suspensions,

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phytosome complexes, inclusion complexes and dendrimer/dimers (42). Lately, pure curcumin nanoparticles have been developed that are 50 times more effective than normal curcumin, with increased bioavailability, instead of carrier-based nano formulations. These curcumin nanoparticles confine tumor-induced Treg cells by hindering several Treg markers and restore immune surveillance in tumor-bearing mice (43). Albeit, nanotechnology based drug delivery system has been confirmed as a major effective and promising approach towards successful cancer therapy but there are certain limitations. Some problems like possibility of drug targeting, drug-loading capacity, in vivo fate of the carrier-molecule conjugates (interactions with the biological microenvironment, rate of disintegration and accumulation in organs), toxic effects of the carrier molecule or its metabolites, its large scale manufacture, stability during long-term storage and overall production costs are difficult to deal with. Particularly, a crucial parameter in the body is the toxic effects of the nano-formulations. Albeit, the carrier materials are examined for toxicity and biocompatibility, nevertheless the qualities of the nano particles often differ from bulk material. Therefore, it is necessary that rigorous and specialized tests take for determining the toxicities of the carrier molecules, its metabolites and surfactants, before approval for use (39). Curcumin emulsions, liposome and phospholipid formulation Eucalyptol-based curcumin microemulsions have extremely high permeability and flux with average solubility of curcumin compared with lots of oleic acid- and esteem oil-based microemulsions (40). The enhanced penetration capacity of this applied curcumin microemulsion formulation have been observed also its effect on the cellular structure of skin. Moreover, a new microemulsion (approximately 10 nm) combination of limonene, polysorbate 80, ethanol and water promotes curcumin presence in skin (9.29–29.99 µg in an area of 0.785 cm2) (41). Coacervation technique in the presence of polymeric non-ionic surfactants prepared Myristic, palmitic, stearic and behenic acids (i.e., fatty acids; FA)-based solid lipid NPs (42). This manner at first weigh down to 28–81% with a 500-nm particle size. After hydrolysis, this diameter size diminished to 300 nm. A stable self-microemulsifying drug delivery system (SMEDDS) containing 20% ethanol, 60% Cremophor RH40® and 20% isopropyl myristate was able to encapsulate 50 mg/ml of curcumin and to discharge it totally in 10 min (43-45). Curcumin microemulsions made ready in the presence of ethyl oleate and isopropyl myristate

result in homogeneous, yellow, transparent solutions, whiles soybean oil and peppermint oil are turbid in nature (45). The emulsion crosslinking method suitable for lung targeting formulated extremely flat surface gelatin microspheres with 75.5% curcumin encapsulation efficiency (45). These spheres are 5–30 µm in diameter, with 50% curcumin discharge within 22 h for urgent remedial effects. Co-administration of curcumin and paclitaxel nanoemulsion formulations are capable of conquering multidrug resistance in SKOV3 (TR) human ovarian adenocarcinoma cells by hampering NF-κB activity, downregulating P-gp and promoting apoptotic answer (46). Moreover, the bioavailability of paclitaxel up to 5.2-fold is increased by curcumin nano emulsion and there is a 3.2-fold increase in its accumulation at the tumor site in an oral administration to SKOV3 tumor-bearing xenograft mice models, that resulted from downregulation of intestinal P-gp and cytochrome P450 3A2 (CYP3A2) protein levels [47]. Liposomes constitute artificial phospholipid vesicles, considered to be biologically safe, biocompatible and preserve drugs from external stimuli. It has been known that a prolonged absorption capacity of curcumin can be obtained by dissolving, mixing or complexing it with several types of phospholipid. Sou et al. (48) have successfully made ready a curcumin lipid formulation using 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and an anionic amphiphilic, L-glutamic acid, N-(3-carboxy-1-oxopropyl)-1,5-dihexadecyl ester (SA). Intravenous administration of this formulation in rats indicated no acute response in circulating blood cells and extremely of the curcumin accumulated in bone marrow and spleen tissues. A recent pharmacokinetic research of solid lipid curcumin NPs in patients with osteosarcoma introduced up to 31.42–41.15 ng/ml of curcumin within 4 h of 2000–4000 mg oral dose treatment (49). More importantly, the patients did not experience any side effects. In another research, solid lipid NPs with 134 nm and 84% encapsulation of curcumin displayed slow discharge of curcumin over a week (50). High oral bioavailability in plasma of male wistar rats is resulted in by this formulation. Curcumin solid lipid NPs at every single oral dose of 1, 12.5, 25 and 50 mg/kg pharmacokinetics in rats attained a maximum concentration (Cmax) of bioavailability in serum 1.00±0.01, 7.87 ± 3.02, 8.00 ± 1.87, and 14.29 ± 0.15 µg/ml, respectively, whiles free curcumin was only present at 0.292 ± 0.06 µg/ml, even at a dose of 50 mg/kg. This enhancement in bioavailability result in improvement of curcumin absorption. A comparative survey showed the uptake of liposome- and serum albumin-loaded curcumin formations in normal spleen lymphocytes and EL4

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lymphoma cells via fluid phase pinocytosis and membrane fusion, respectively (51). Curcumin-loaded liposomal formulation was a more useful delivery transporter and further noteworthy absorption and fluorescence levels in lymphoma cells compared with normal cells. Li et al. (52) assessed the lipid curcumin ratio (10:1 wt./wt.) on different pancreatic carcinoma cell lines, including ASPC-1, BxPC-3, Capan-1, Capan-2, HS766-T and MiapaCa2, and showed an inhibition concentration of IC50 at 2.0–37.8 µM, whiles IC90 was 6.75–94.5 µM, as determined by cytotoxicity. Recently, curcumin was successfully inserted in egg-phosphatidylcholine (EPC) liposomes at a 1:14 molar ratio (curcumin:liposome). A twofold improvement in concentration of curcumin was present in rat plasma with the lecithin curcumin formulation compared with a curcumin and curcumin-lecithin mixture after recommending of a single oral dose of 100 mg curcumin/kg body weight [53]. Narayanan et al. (54) provided an interesting vision of the use of curcumin and resveratrol in liposome to consider their combined effects on: (i) cell progress, apoptosis and the cell cycle; and (ii) on activated p-Akt, cyclin D1, mammalian target of rapamycin (m-TOR) and androgen receptor (AR) proteins involved in tumor progression of PTEM-CaP8 prostate cancer cells. Totally, this combined formulation remarkably reduced incidence of prostatic adenocarcinoma in vivo . Transferrin-solid lipid NPs maintained 83% of curcumin for 6 months and particularly, targeted MCF-7 breast cancer cells four- and five fold in 24 and 48 h therapy, respectively (55). Transferrin-mediated endocytosis was verified, which promotes a kind of reactive oxygen (ROS) and time-dependant apoptosis by transferrin-solid lipid curcumin NPs. Curcumin structural aspects facilitated nanodisk NPs containing a disk-shaped lipid bilayer formation generally stabilized by an apolipoprotein scaffold (56). The effectiveness of anticancer properties of this lipid curcumin formulation in human hepatocellular carcinoma (HepG2) was significant over that of free curcumin. polymeric NPs. Poly (lactic-co-glycolic acid) (PLGA) is an extensive choice in the production of a variety of biomedical devices due to the its biodegradability and biocompatibility. Several different types of PLGA NP for curcumin encapsulation have been explored because of producing a safe carrier. Curcumin-encapsulated PLGA NPs has been prepared to use a simple solid–oil–water solvent evaporation method (57). with the surfactant concentration and sonication time control the particle size. Afterward, solvent evaporation method is designed to regulate the curcumin-encapsulated PLGA NPs via a lower

particle size, increased intracellular uptake and antibody conjugation aspects (58). Grabovac and Bernkop studied first the development of surface-modified PLGA NPs with a thiolated chitosan [59]. Level functionalization of curcumin-loaded PLGA NPs by a bis (sulfosuccinimidyl) suberate (BS3) has facilitated conjugation of annexin A2 and resulted in an effective target treatment of curcumin to annexin A2-positive MDA-MB-231 cancer cells [60]. Shahani and Panyam (61) planned a sustained and injectable microparticle formulation with higher curcumin loading capacity (i.e. 38.1 mg/100 mg of particles; 76.2% encapsulation efficiency) contrasted with many formulations. A developed glutathione-s-transferase (GST) activity in liver was distinguished with injectable microparticles and this observed phenomenon was steady over 4 weeks. Usually a potent endogenous defense mechanism against carcinogens is demonstrated by GST activity. In vivo researches in mice which applied this formulation, has resulted a tenfold increase in blood, brain and lungs curcumin, compared with which dissolved in PEG 400 formulation (62). Curcumin-loaded PLGA has been designed by Tsai et al. (63) which increased the half-life of curcumin in the cerebral cortex and hippocampus significantly from 2.32 to 19.9 and 7.56 to 16.7 min, respectively. Moreover, retention time values of the cerebral cortex and the hippocampus were increased almost 2.0- and 1.8-fold, respectively. With this nano-formulation, the curcumin plasma levels were slightly higher. Nano formulations based on dextran sulfate-chitosan are considered to be biocompatible materials which can be applied for oral, intravenous and controlled delivery aims. Other research quantified the cellular uptake of curcumin encapsulated in dextran sulfate-chitosan NPs with applying a spectrophotometric method in L929, MCF-7, PC3 and MG 63 cells (64). Moreover, a cytotoxicity evaluation and fluorescence-activated cell sorting (FACS) investigation proposed that anticancer activity of this formulation is high in MCF-7 compared with other cancer cells. A curcumin analog encapsulated in polycaprolactone (PCL) NPs (approximately 650 nm) controlled intravenously to male Wistar rats demonstrated higher intracellular surface in liver cells, which proposed that this formulation can be used to target the liver (65). Multi-drug resistance cancer cells (K562 cells) are treated more effectively by co-encapsulation of curcumin and doxorubicin in polymer NPs (66). Primary curcumin release from NPs downregulated MDR1 and BCL-2 expression and hindered the nuclear efflux mechanism; the subsequent release of doxorubicin provoked cancer cell death. A patented technology described by synthesis of curcumin-encapsulated chitosan NPs demonstrated to be safe

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in mice and rat researches at a dose of 4 mg and 40 mg of formulations, respectively, for 14 days (67). Micelles A micelle, regularly is a surfactant molecule aggregate dispersed in a liquid colloid. It is a nanosized vesicular membrane which became it soluble in water by gathering the hydrophilic heads outer surface in contact with the solvent and hydrophobic tails inside and is known as emulsifications. Micelles are lipid molecules which organize themselves in a spherical form in aqueous solutions with a very narrow range from 10 to 100 nm in size, that makes them more stable through dilution in biological fluids (68). The structure or morphology of micelles is from amphiphilic block copolymers both spherical, rodlike, and tarlike, as well as vesicles. The self-assembly of amphiphilic block copolymer is a reversible method, and the shape differs with the copolymers' composition and length ratio (69). The performance of micelles is based on amphiphilic block copolymers, that come together to form a nanosized core/shell structure in aqueous media. The hydrophilic shell surface stabilizes the hydrophobic core and result in the polymers water soluble while the hydrophobic core area distributes like a pool for hydrophobic drugs. Water-insoluble drugs such as curcumin can serve by polymeric micelles as transmitters, which can raise the drug's efficiency by targeting certain cells or organs so that, fewer drugs gather in healthy tissues and their toxicity decreases and occasionally higher doses can be administered (70). With this attention, Liu et al. (71) prepared curcumin-loaded biodegradable self-assembled polymeric micelles by solid dispersion method was simple and easy to scale up and has overcome the poor water solubility of curcumin. Release profile, between quick release of free curcumin and much slower and sustained release of curcumin-loaded micelles indicated a significant difference. Moreover, Raveendran et al. (72) investigated that preparation of curcumin-loaded micelles based on amphiphilic Pluronic/polycaprolactone block copolymer, has been confirmed to be efficient in increasing curcumin's aqueous solubility. Other researches also evaluated on highly surface-active compounds such as poloxamer or Pluronic which can self-assemble into spherical micelle. In vitro results indicated that spherical curcumin-loaded mixed micelles might serve as potential nanocarriers to amend the solubility and biological activity of curcumin (73–74). In another research, encapsulation within the micelles increased the aqueous solubility of curcumin (75). Solubilization was directly related to the compatibility between the solubilizate and polycaprolactone as

determined by the Flory-Huggins interaction parameter. Curcumin tended to interact with polycaprolactone serving as a core embraced by polyethylene glycol as a shell was proposed by molecular modeling research. Moreover, the structure of modified ε-polylysine micelles and their utilization in improving cellular antioxidant activity of curcuminoids was shown by Yu et al. (76). Results of these studies showed that curcuminoids can improve their water solubility and cellular antioxidative activity compared with free curcuminoids when encapsulated via modified ε-polylysine micelles. It was suggested that for delivering poorly soluble drugs such as curcumin may use these new biopolymer micelles. To overcome the poor water solubility of curcumin, another synthesized curcumin in sodium dodecyl sulfate and cetyltrimethylammonium bromide has indicated antioxidative effects of curcumin analogues against the free-radical-induced peroxidation of linoleic acid in these micelles (77, 78). Due to their higher solubility than free curcumin, kinetic analysis of the antioxidation processes proved that these compounds showed incredibly higher antioxidative activity (77). Several issues indicated micelle stability, the rateof copolymer biodegradation, and drug diffusion control release from micelles. By the way,the potential of the two most common Pluronic triblock copolymer micelles, Pluronic F127 and F68, for curcumin encapsulation efficiency and stability was reported by Sahu et al. (79). Pluronic F127 indicated better encapsulation efficiency and good stability for long-term storage than Pluronic F68. Atomic force microscopy (AFM) research demonstrated that the drug-encapsulated micelles are spherical in shape with diameters below 100 nm. Pluronic-encapsulated curcumin showed slower and sustained release of curcumin from the micelles and substantial anticancer activity in comparison with free curcumin during in vitro cytotoxicity study. Moreover, a natural protein core-based polymeric micelle were reported by Podaralla et al. (80) which applied for delivering of hydrophobic anticancer drugs, specifically curcumin. Also it was produced new biodegradable micelles by conjugating methoxy polyethylene glycol and zein, a biodegradable hydrophobic plant protein which then encapsulating with curcumin. Polyethylene glycol zein micelles maintained the curcumin release up to 24 h in vitro and remarkably enhanced its aqueous solubility and stability with 3-fold reduction in IC50 of curcumin. So, whereas the curcumin is finely protected from possible inactivation by their micellar environment, its retention and bioavailability can also be extended. Because of modifying the

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pharmacokinetics of curcumin, poly(D,L-lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly(D,L-lactide-co-glycolide) (PLGA-PEG-PLGA) with micelles were synthesized by Song et al (81). PLGA-PEG-PLGA micelles provided higher area under the concentration curve (AUC) and increased residence time, clearance, and distribution half-life in comparison with curcumin solution. The extension of half-life, enhanced residence time, and decreased total clearance showed which curcumin-loaded micelles could prolong acting time of curcumin in vivo. These results may be in relation with curcumin location within the micelles and enhanced viscosity of copolymer solution at body temperature. The change of AUC proved that the curcumin-loaded micelles provided higher bioavailability than curcumin solution, and the biodistribution research indicated that the micelles had diminished drug uptake by liver and spleen and intensified drug distribution in lung and brain. These outcomes proposed that PLGA-PEG-PLGA micelles would be a potential bearer for curcumin. Moreover,the pharmacokinetics of both solubilized curcumin and its polymeric micellar formulation in rats via using a simple, rapid, and reliable HPLC method were proved by Ma et al. (73). They concluded that curcumin's half-life and distribution volume increased by encapsulation of curcumin in the polymeric micellar formulation. Moreover, physicochemical characteristics, concentration, and location within the micelles can be affected by curcumin-micelles. The polymeric micelles have a prolonged circulation time because of the small size and hydrophilic layer which reduces the drug uptake via the mononuclear phagocyte system (82). Encapsulated curcumin in cationic micelles suppresses alkaline hydrolysis that was investigated in three types of micelles composed of the cationic surfactants cetyltrimethylammonium bromide (CTAB) and dodecyltrimethylammonium bromide (DTAB) and the anionic surfactant sodium dodecyl sulfate (SDS) which were reported by Leung et al. (83). Curcumin underwent rapid decomposition in the SDS micellar solution with alkaline hydrolysis at pH of 13, whiles it was significantly suppressed with performance of suppression close to 90% in the presence of either CTAB or DTAB micelles. The results of the fluorescence spectroscopic studies showed that curcumin is separated from the SDS micelles to the aqueous phase at this pH while curcumin stays on encapsulated in CTAB and DTAB micelles at pH 13. The lack of encapsulation and stability in the SDS micellar solution led rapid hydrolysis of curcumin. Other curcumin-loaded micelles properties were indicated by some other studies. The sensitive fluorometric method for the

determination of curcumin using the increase of mixed micelle was introduced by Wang et al. (84). This method had the benefits of high sensitivity, selectivity, and stability. Mixed micelle of sodium dodecylbenzenesulfonate and cetyltrimethylammonium bromide (SDBS-CTAB) greatly increased the fluorescence of curcumin. This research showed that fluorescence quantum yield of curcumin in SDBS-CTAB micelle was about 55-fold bigger than that of aqueous solution containing 1.0% ethanol, that was in agreement with their fluorescence intensity ratio. As a result, curcumin could be used as a fluorophore in fluorescence polarization anisotropy measurement in order to critical micellar concentration of surfactant and to check their interaction. Moreover, femtosecond fluorescence upconversion experiments on the naturally occurring medicinal pigment, curcumin, in anionic, cationic, and neutral micelles were performed by Adhikary et al. (85). These micelles were formed of SDS, dodecyltrimethylammonium bromide (DTAB), and Triton X-100. They showed the curcumin's excited-state kinetics in micelles with fast (3–8 ps) and slow (50–80 ps) components. While deuteration of curcumin had a negligible effect on the fast component, the slow component displayed a pronounced isotope impact of approximately 1.6, it shows that micelle-captured curcumin undergoes excited-state intramolecular hydrogen atom transfer. In addition, curcumin to phosphatidylcholine micelles followed by fluorescence measurements had been attached by Began et al. (86). Curcumin in aqueous solution did not prevent dioxygenation of fatty acids by lipoxygenase 1, but it prevented the oxidation of fatty acids when bound to phosphatidylcholine micelles. Results showed that for 50% inhibition of linoleic acid peroxidation requires 8.6 µM of curcumin bound to the phosphatidylcholine micelles. Line Weaver-Burk plan analysis had demonstrated that curcumin is a competitive inhibitor of lipoxygenase 1 with Ki of 1.7 μM for linoleic acid and 4.3 μM for arachidonic acid, respectively. Using spectroscopic measurement, they showed that the inhibition of lipoxygenase 1 activity by curcumin could be because of binding to active center iron and curcumin after binding to the phosphatidylcholine micelles acts as an inhibitor of lipoxygenase 1. In a recent research,with fluorescent probe determined the critical micelle concentration of the amphiphilic polymer. Results demonstrated that Pluronic/polycaprolactone micelles may be an acceptable candidate for curcumin delivery to cancer cells of colorectal adenocarcinoma (72). In another pharmacokinetic study, higher concentration and longer retention time in plasma

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and tumor sites were indicated by curcumin micelles , so they had stronger inhibitory effects on proliferation, migration, invasion, and tube formation of carcinoma cells than free curcumin; for instance, curcumin micelles were shown to be more effective, probably because of higher concentration in preventing tumor growth and long-term survival in both subcutaneous and pulmonary metastatic tumor models (87). Check the impact of micelles on cytotoxicity of curcumin, specifically in cancer therapy, in vitro research by Raveendran et al. (72) indicated that Pluronic/polycaprolactone micelles could be an acceptable candidate for curcumin delivery to cancer cells due to the cytotoxicity and cellular uptake of the curcumin-loaded micelles in colorectal adenocarcinoma cells. The study by Wang et al. [88] showed that the encapsulated curcumin keeps its potent antitumor effects; Nevertheless, curcumin-loaded micelles were more efficient in inhibiting tumor growth and spontaneous pulmonary metastasis in subcutaneous 4T1 breast tumor model and long-term survival of tumor-bearing mice. Tumors of curcumin-loaded micelle-treated mice had more apoptotic cells, fewer microvessels, and fewer proliferation-positive cells also were showed by Immunofluorescent and immunohistochemical research (88). Moreover, methoxypolyethylene glycol-polylactic acid (mPEG-PLA) micelle to several curcumin molecules had been conjugated by Yang et al. (89); the cytotoxicity research outcomes demonstrated that the effect of IC50 of mPEG-PLA-Tris-curcumin on human hepatocellular carcinoma cells was similar to unmodified curcumin. The cellular uptake research showed that these bearers can successfully transport the drug to the cytoplasm of hepatic cells. Micelles containing several drug molecules were an effective means to increase loading and intracellular transfer of low-potency curcumin (89). Moreover,the curcumin encapsulated in methoxy poly(ethylene glycol)/poly-epsilon-caprolactone diblock copolymeric (MePEG/PCL) micelle, with change the copolymer ratio (40 : 60 MePEG/PCL ratio was selected due to its high encapsulation), had expanded bioavailability because of strong uptake, 2.95 times more, with comparative cytotoxic effects by induction of apoptosis in contrary with unmodified curcumin at equimolar concentrations were reported by Mohanty et al. (90). Generally, these data certainly demonstrated the commitment of a micellar system for efficient solubilization, stabilization, and controlled delivery of the hydrophobic drug, such as curcumin, for cancer treatment. Briefly, curcumin-loaded micelles can increase the drug's efficiency by targeting definite cells and outcome in less drug aggregation in

healthy tissues and decrease of toxicity. Curcumin's aqueous solubility and much slower and sustained release of drug created by curcumin-loaded micelles also obtain for use in several conditions. The survival and bioavailability of curcumin could be high since the curcumin is preserved from possible inactivation by its micellar surroundings. Locating the curcumin in the micelles can also increase half-life and residence time and reduce total clearance leading to lengthening of acting time of curcumin. Curcumin micelles could be impressed by physicochemical features containing their size and electrical charges, concentration, and location within the micelles. Conclusion Curcumin is found to be an extremely helpful anti-cancer factor, targeting different paths connected with cancer development. Researchers continue to disclose new ways of its action and its interaction that with the immune system is coming out as an important factor to its anti-cancer properties. The need for tumor cells to evade the immune system during successful tumor progression in the body is now considered a new characteristic of cancer. Several advanced studies in the past decade have gradually published curcumin as a powerful immune-modulator. Albeit, several reports have proposed a general immunosuppressive role of curcumin and its capability to diminish cell proliferation in immune cell in isolation; specific reports show that curcumin increases anti-tumor immunity via different mechanisms, as discussed in this review. So modulation of the immune system shows to be another important strategy by which curcumin neutralizes cancer growth. This furthermore claims its effect as an anti-cancer factor and points out the need to develop it as an adjuvant chemotherapeutic factor. This necessitates the improvement of nano-based strategies for suitable delivery and increased bioavailability of curcumin, that may eventually lead to its use as an appropriate chemotherapeutic factor. Conflict of interest The authors report no conflicts of interest. Financial disclosure No financial supports have been granted by any agency to conduct this publication.

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